Wei Cao MPhil , Guodong Chen PhD , Lijun Wu PhD , K.N. Yu PhD , Mingyu Sun BA , Miaomiao Yang MPhil , Yanyi Jiang PhD , Yuan Jiang PhD , Yuan Xu MPhil , Shengjie Peng MPhil , Wei Han PhD
{"title":"电离辐射通过诱导气真皮蛋白e介导的肿瘤细胞热亡触发抗肿瘤免疫","authors":"Wei Cao MPhil , Guodong Chen PhD , Lijun Wu PhD , K.N. Yu PhD , Mingyu Sun BA , Miaomiao Yang MPhil , Yanyi Jiang PhD , Yuan Jiang PhD , Yuan Xu MPhil , Shengjie Peng MPhil , Wei Han PhD","doi":"10.1016/j.ijrobp.2022.07.1841","DOIUrl":null,"url":null,"abstract":"<div><h3>Purpose</h3><p><span>To understand pyroptosis induced by </span>ionizing radiation<span> and its implications for radiation therapy, we explored the involved factors, possible mechanisms of radiation-induced pyroptosis and consequent antitumor immunity.</span></p></div><div><h3>Methods and Materials</h3><p><span><span>The occurrence of pyroptosis was assessed by cell morphology, lactate dehydrogenase<span> release, Annexin V/PI staining and the cleavage of Gasdermin E (GSDME). Cell radiosensitivity was tested with MTT and colony survival assays. </span></span>Xenograft tumor volume, Ki-67, CD8</span><sup>+</sup> lymphocytes, and ELISA were used to evaluate the effect of GSDME on tumor suppression after irradiation.</p></div><div><h3>Results</h3><p>Irradiation induced pyroptosis in GSDME high-expressing tumor cell lines<span> covering lung, liver, breast, and glioma<span> cancers. Cleavage of GSDME occurred in a dose- and time-dependent manner after irradiation, and pyroptosis could be induced by various kinds of irradiation. The combination of chemotherapy drugs<span> for DNA damage (cisplatin or etoposide) or demethylation<span> (decitabine or azacytidine) and irradiation significantly enhanced the occurrence of pyroptosis. Moreover, we revealed that the Caspase 9/Caspase 3/GSDME pathway was involved in irradiation-induced pyroptosis. Notably, enhanced tumor suppression was observed in Balb/c mice bearing GSDME-overexpressing 4T1 tumors compared with those bearing vector tumors for the promotion of antitumor immunity, which was manifested as distinctly elevated levels of cytotoxic T lymphocytes and release of the related cytokines rather than the direct effect of pyroptosis on tumor cell radiosensitivity.</span></span></span></span></p></div><div><h3>Conclusions</h3><p>As an immunogenic cell death caused by radiation, pyroptosis promotes antitumor immunity after irradiation. Our findings may provide new insights to improve the efficacy of tumor radiation therapy.</p></div>","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":"115 2","pages":"Pages 440-452"},"PeriodicalIF":6.4000,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"17","resultStr":"{\"title\":\"Ionizing Radiation Triggers the Antitumor Immunity by Inducing Gasdermin E-Mediated Pyroptosis in Tumor Cells\",\"authors\":\"Wei Cao MPhil , Guodong Chen PhD , Lijun Wu PhD , K.N. Yu PhD , Mingyu Sun BA , Miaomiao Yang MPhil , Yanyi Jiang PhD , Yuan Jiang PhD , Yuan Xu MPhil , Shengjie Peng MPhil , Wei Han PhD\",\"doi\":\"10.1016/j.ijrobp.2022.07.1841\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Purpose</h3><p><span>To understand pyroptosis induced by </span>ionizing radiation<span> and its implications for radiation therapy, we explored the involved factors, possible mechanisms of radiation-induced pyroptosis and consequent antitumor immunity.</span></p></div><div><h3>Methods and Materials</h3><p><span><span>The occurrence of pyroptosis was assessed by cell morphology, lactate dehydrogenase<span> release, Annexin V/PI staining and the cleavage of Gasdermin E (GSDME). Cell radiosensitivity was tested with MTT and colony survival assays. </span></span>Xenograft tumor volume, Ki-67, CD8</span><sup>+</sup> lymphocytes, and ELISA were used to evaluate the effect of GSDME on tumor suppression after irradiation.</p></div><div><h3>Results</h3><p>Irradiation induced pyroptosis in GSDME high-expressing tumor cell lines<span> covering lung, liver, breast, and glioma<span> cancers. Cleavage of GSDME occurred in a dose- and time-dependent manner after irradiation, and pyroptosis could be induced by various kinds of irradiation. The combination of chemotherapy drugs<span> for DNA damage (cisplatin or etoposide) or demethylation<span> (decitabine or azacytidine) and irradiation significantly enhanced the occurrence of pyroptosis. Moreover, we revealed that the Caspase 9/Caspase 3/GSDME pathway was involved in irradiation-induced pyroptosis. Notably, enhanced tumor suppression was observed in Balb/c mice bearing GSDME-overexpressing 4T1 tumors compared with those bearing vector tumors for the promotion of antitumor immunity, which was manifested as distinctly elevated levels of cytotoxic T lymphocytes and release of the related cytokines rather than the direct effect of pyroptosis on tumor cell radiosensitivity.</span></span></span></span></p></div><div><h3>Conclusions</h3><p>As an immunogenic cell death caused by radiation, pyroptosis promotes antitumor immunity after irradiation. Our findings may provide new insights to improve the efficacy of tumor radiation therapy.</p></div>\",\"PeriodicalId\":14215,\"journal\":{\"name\":\"International Journal of Radiation Oncology Biology Physics\",\"volume\":\"115 2\",\"pages\":\"Pages 440-452\"},\"PeriodicalIF\":6.4000,\"publicationDate\":\"2023-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"17\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Radiation Oncology Biology Physics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0360301622025962\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Radiation Oncology Biology Physics","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0360301622025962","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Ionizing Radiation Triggers the Antitumor Immunity by Inducing Gasdermin E-Mediated Pyroptosis in Tumor Cells
Purpose
To understand pyroptosis induced by ionizing radiation and its implications for radiation therapy, we explored the involved factors, possible mechanisms of radiation-induced pyroptosis and consequent antitumor immunity.
Methods and Materials
The occurrence of pyroptosis was assessed by cell morphology, lactate dehydrogenase release, Annexin V/PI staining and the cleavage of Gasdermin E (GSDME). Cell radiosensitivity was tested with MTT and colony survival assays. Xenograft tumor volume, Ki-67, CD8+ lymphocytes, and ELISA were used to evaluate the effect of GSDME on tumor suppression after irradiation.
Results
Irradiation induced pyroptosis in GSDME high-expressing tumor cell lines covering lung, liver, breast, and glioma cancers. Cleavage of GSDME occurred in a dose- and time-dependent manner after irradiation, and pyroptosis could be induced by various kinds of irradiation. The combination of chemotherapy drugs for DNA damage (cisplatin or etoposide) or demethylation (decitabine or azacytidine) and irradiation significantly enhanced the occurrence of pyroptosis. Moreover, we revealed that the Caspase 9/Caspase 3/GSDME pathway was involved in irradiation-induced pyroptosis. Notably, enhanced tumor suppression was observed in Balb/c mice bearing GSDME-overexpressing 4T1 tumors compared with those bearing vector tumors for the promotion of antitumor immunity, which was manifested as distinctly elevated levels of cytotoxic T lymphocytes and release of the related cytokines rather than the direct effect of pyroptosis on tumor cell radiosensitivity.
Conclusions
As an immunogenic cell death caused by radiation, pyroptosis promotes antitumor immunity after irradiation. Our findings may provide new insights to improve the efficacy of tumor radiation therapy.
期刊介绍:
International Journal of Radiation Oncology • Biology • Physics (IJROBP), known in the field as the Red Journal, publishes original laboratory and clinical investigations related to radiation oncology, radiation biology, medical physics, and both education and health policy as it relates to the field.
This journal has a particular interest in original contributions of the following types: prospective clinical trials, outcomes research, and large database interrogation. In addition, it seeks reports of high-impact innovations in single or combined modality treatment, tumor sensitization, normal tissue protection (including both precision avoidance and pharmacologic means), brachytherapy, particle irradiation, and cancer imaging. Technical advances related to dosimetry and conformal radiation treatment planning are of interest, as are basic science studies investigating tumor physiology and the molecular biology underlying cancer and normal tissue radiation response.